PROJECT ABSTRACT Pelvic floor disorders (PFDs) such as stress urinary incontinence (SUI) and/or pelvic organ prolapse (POP) are common and costly situation in women with a lifetime risk of surgical repair of 20%. For the treatment of SUI, placement of a mid-urethral sling manufactured from polypropylene mesh is the most widely used procedure. For POP, polypropylene meshes are also used to improve on the high failure rates (up to 40% at 2 years; 60% at 7 years) of native tissue repairs. Unfortunately, these meshes are associated with mesh related complications, most commonly exposure of mesh through vaginal epithelium and pain. These complications occur more frequently in diabetic women, roughly 3 times more in comparison to the general population. However, research into mechanisms by which diabetes increases the risks of mesh complications has been scant. It is estimated that among the 350,000 women who receive meshes annually in the US, over 14% are known diabetics. Since the number of women undergoing SUI and POP surgeries is predicted to increase by 50% by 2050, more diabetic women will receive meshes. Therefore, insight into the mechanisms has the potential to markedly impact health care. Typical of any host responses to a foreign material, studies from our group have shown that macrophage is the key cell type that mediates the responses to meshes. However, an irreversible aging process of macrophages (senescence) is accelerated by high level of blood glucose in diabetic patients. These premature senescent macrophages are associated with functional deficit in phagocytosis and regulation of immune response to foreign bodies such as mesh. In addition, we found that macrophage phenotypic transition from pro- inflammatory M1 to pro-healing M2 was impaired in mesh-tissue specimens excised from diabetic women with mesh complications. Based on the findings from our group and others, we hypothesized that macrophage senescence associated dysfunction with impaired M1 to M2 transition is the primary mechanism leading to the increased risk of mesh complications in diabetic women. We propose the following aims to test our hypothesis in a middle-aged diabetic rat model: Aim 1: To determine the impact of diabetes on the host response and mesh-tissue incorporation following mesh implantation; Aim 2: To determine the impact of diabetes on the acquisition of macrophage senescence and HDAC3/IL-4 signaling pathway in macrophages at the mesh implantation site; Aim 3: To improve mesh incorporation with tissue by replacing dysfunctional macrophages with monocytes isolated from healthy rats or promoting M1 to M2 transition via selective HDAC3 inhibition mediated by a novel viral vector (AAV-CD68p-shHDAC3). The data from this proposal will offer the following innovative deliverables: 1) address the knowledge gap by defining the mechanism by which diabetes increases the risk of mesh complications; 2) develop novel macrophage-based therapies that is clinically translatable with potential applicability to other devices.